Posts tagged neurons
Articles and news from the latest research reports.
Study finds a patchwork of genetic variation in the brain
It was once thought that each cell in a person’s body possesses the same DNA code and that the particular way the genome is read imparts cell function and defines the individual. For many cell types in our bodies, however, that is an oversimplification. Studies of neuronal genomes published in the past decade have turned up extra or missing chromosomes, or pieces of DNA that can copy and paste themselves throughout the genomes.
The only way to know for sure that neurons from the same person harbor unique DNA is by profiling the genomes of single cells instead of bulk cell populations, the latter of which produce an average. Now, using single-cell sequencing, Salk Institute researchers and their collaborators have shown that the genomic structures of individual neurons differ from each other even more than expected. The findings were published November 1, 2013, in Science.
"Contrary to what we once thought, the genetic makeup of neurons in the brain aren’t identical, but are made up of a patchwork of DNA," says corresponding author Fred Gage, Salk’s Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
In the study, led by Mike McConnell, a former junior fellow in the Crick-Jacobs Center for Theoretical and Computational Biology at the Salk, researchers isolated about 100 neurons from three people posthumously. The scientists took a high-level view of the entire genome—looking for large deletions and duplications of DNA called copy number variations or CNVs—and found that as many as 41 percent of neurons had at least one unique, massive CNV that arose spontaneously, meaning it wasn’t passed down from a parent. The CNVs are spread throughout the genome, the team found.
The miniscule amount of DNA in a single cell has to be chemically amplified many times before it can be sequenced. This process is technically challenging, so the team spent a year ruling out potential sources of error in the process.
"A good bit of our study was doing control experiments to show that this is not an artifact," says Gage. "We had to do that because this was such a surprise—finding out that individual neurons in your brain have different DNA content."
The group found a similar amount of variability in CNVs within individual neurons derived from the skin cells of three healthy people. Scientists routinely use such induced pluripotent stem cells (iPSCs) to study living neurons in a culture dish. Because iPSCs are derived from single skin cells, one might expect their genomes to be the same.
"The surprising thing is that they’re not," says Gage. "There are quite a few unique deletions and amplifications in the genomes of neurons derived from one iPSC line."
Interestingly, the skin cells themselves are genetically different, though not nearly as much as the neurons. This finding, along with the fact that the neurons had unique CNVs, suggests that the genetic changes occur later in development and are not inherited from parents or passed to offspring.
It makes sense that neurons have more diverse genomes than skin cells do, says McConnell, who is now an assistant professor of biochemistry and molecular genetics at the University of Virginia School of Medicine in Charlottesville. “The thing about neurons is that, unlike skin cells, they don’t turn over, and they interact with each other,” he says. “They form these big complex circuits, where one cell that has CNVs that make it different can potentially have network-wide influence in a brain.”
Spontaneously occurring CNVs have also been linked to risk for brain disorders such as schizophrenia and autism, but those studies usually pool many blood cells. As a result, the CNVs uncovered in those studies affect many if not all cells, which suggests that they arise early in development.
The purpose of CNVs in the healthy brain is still unclear, but researchers have some ideas. The modifications might help people adapt to new surroundings encountered over a lifetime, or they might help us survive a massive viral infection. The scientists are working out ways to alter genomic variability in iPSC-derived neurons and challenge them in specific ways in the culture dish.
Cells with different genomes probably produce unique RNA and then proteins. However, for now, only one sequencing technology can be applied to a single cell.
"If and when more than one method can be applied to a cell, we will be able to see whether cells with different genomes have different transcriptomes (the collection of all the RNA in a cell) in predictable ways," says McConnell.
In addition, it will be necessary to sequence many more cells, and in particular, more cell types, notes corresponding author Ira Hall, an associate professor of biochemistry and molecular genetics at the University of Virginia. “There’s a lot more work to do to really understand to what level we think the things we’ve found are neuron-specific or associated with different parameters like age or genotype,” he says.
(Source: salk.edu)
Neuroscientists Determine How Treatment for Anxiety Disorders Silences Fear Neurons
Excessive fear can develop after a traumatic experience, leading to anxiety disorders such as post-traumatic stress disorder and phobias. During exposure therapy, an effective and common treatment for anxiety disorders, the patient confronts a fear or memory of a traumatic event in a safe environment, which leads to a gradual loss of fear. A new study in mice, published online today in Neuron, reports that exposure therapy remodels an inhibitory junction in the amygdala, a brain region important for fear in mice and humans. The findings improve our understanding of how exposure therapy suppresses fear responses and may aid in developing more effective treatments. The study, led by researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts, was partially funded by a New Innovator Award from the Office of the Director at the National Institutes of Health.
A fear-inducing situation activates a small group of neurons in the amygdala. Exposure therapy silences these fear neurons, causing them to be less active. As a result of this reduced activity, fear responses are alleviated. The research team sought to understand how exactly exposure therapy silences fear neurons.
The researchers found that exposure therapy not only silences fear neurons but also induces remodeling of a specific type of inhibitory junction, called the perisomatic synapse. Perisomatic inhibitory synapses are connections between neurons that enable one group of neurons to silence another group of neurons. Exposure therapy increases the number of perisomatic inhibitory synapses around fear neurons in the amygdala. This increase provides an explanation for how exposure therapy silences fear neurons.
“The increase in number of perisomatic inhibitory synapses is a form of remodeling in the brain. Interestingly, this form of remodeling does not seem to erase the memory of the fear-inducing event, but suppresses it,” said senior author, Leon Reijmers, Ph.D., assistant professor of neuroscience at Tufts University School of Medicine and member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.
Reijmers and his team discovered the increase in perisomatic inhibitory synapses by imaging neurons activated by fear in genetically manipulated mice. Connections in the human brain responsible for suppressing fear and storing fear memories are similar to those found in the mouse brain, making the mouse an appropriate model organism for studying fear circuits.
Mice were placed in a box and experienced a fear-inducing situation to create a fear response to the box. One group of mice, the control group, did not receive exposure therapy. Another group of mice, the comparison group, received exposure therapy to alleviate the fear response. For exposure therapy, the comparison group was repeatedly placed in the box without experiencing the fear-inducing situation, which led to a decreased fear response in these mice. This is also referred to as fear extinction.
The researchers found that mice subjected to exposure therapy had more perisomatic inhibitory synapses in the amygdala than mice who did not receive exposure therapy. Interestingly, this increase was found around fear neurons that became silent after exposure therapy.
“We showed that the remodeling of perisomatic inhibitory synapses is closely linked to the activity state of fear neurons. Our findings shed new light on the precise location where mechanisms of fear regulation might act. We hope that this will lead to new drug targets for improving exposure therapy,” said first author, Stéphanie Trouche, Ph.D., a former postdoctoral fellow in Reijmers’ lab at Tufts and now a medical research council investigator scientist at the University of Oxford in the United Kingdom.
“Exposure therapy in humans does not work for every patient, and in patients that do respond to the treatment, it rarely leads to a complete and permanent suppression of fear. For this reason, there is a need for treatments that can make exposure therapy more effective,” Reijmers added.
(Source: now.tufts.edu)
Synaptic transistor learns while it computes
It doesn’t take a Watson to realize that even the world’s best supercomputers are staggeringly inefficient and energy-intensive machines.
Our brains have upwards of 86 billion neurons, connected by synapses that not only complete myriad logic circuits; they continuously adapt to stimuli, strengthening some connections while weakening others. We call that process learning, and it enables the kind of rapid, highly efficient computational processes that put Siri and Blue Gene to shame.
Materials scientists at the Harvard School of Engineering and Applied Sciences (SEAS) have now created a new type of transistor that mimics the behavior of a synapse. The novel device simultaneously modulates the flow of information in a circuit and physically adapts to changing signals.
Exploiting unusual properties in modern materials, the synaptic transistor could mark the beginning of a new kind of artificial intelligence: one embedded not in smart algorithms but in the very architecture of a computer. The findings appear in Nature Communications.
“There’s extraordinary interest in building energy-efficient electronics these days,” says principal investigator Shriram Ramanathan, associate professor of materials science at Harvard SEAS. “Historically, people have been focused on speed, but with speed comes the penalty of power dissipation. With electronics becoming more and more powerful and ubiquitous, you could have a huge impact by cutting down the amount of energy they consume.”
The human mind, for all its phenomenal computing power, runs on roughly 20 Watts of energy (less than a household light bulb), so it offers a natural model for engineers.
“The transistor we’ve demonstrated is really an analog to the synapse in our brains,” says co-lead author Jian Shi, a postdoctoral fellow at SEAS. “Each time a neuron initiates an action and another neuron reacts, the synapse between them increases the strength of its connection. And the faster the neurons spike each time, the stronger the synaptic connection. Essentially, it memorizes the action between the neurons.”
In principle, a system integrating millions of tiny synaptic transistors and neuron terminals could take parallel computing into a new era of ultra-efficient high performance.
While calcium ions and receptors effect a change in a biological synapse, the artificial version achieves the same plasticity with oxygen ions. When a voltage is applied, these ions slip in and out of the crystal lattice of a very thin (80-nanometer) film of samarium nickelate, which acts as the synapse channel between two platinum “axon” and “dendrite” terminals. The varying concentration of ions in the nickelate raises or lowers its conductance—that is, its ability to carry information on an electrical current—and, just as in a natural synapse, the strength of the connection depends on the time delay in the electrical signal.
Structurally, the device consists of the nickelate semiconductor sandwiched between two platinum electrodes and adjacent to a small pocket of ionic liquid. An external circuit multiplexer converts the time delay into a magnitude of voltage which it applies to the ionic liquid, creating an electric field that either drives ions into the nickelate or removes them. The entire device, just a few hundred microns long, is embedded in a silicon chip.
The synaptic transistor offers several immediate advantages over traditional silicon transistors. For a start, it is not restricted to the binary system of ones and zeros.
“This system changes its conductance in an analog way, continuously, as the composition of the material changes,” explains Shi. “It would be rather challenging to use CMOS, the traditional circuit technology, to imitate a synapse, because real biological synapses have a practically unlimited number of possible states—not just ‘on’ or ‘off.’”
The synaptic transistor offers another advantage: non-volatile memory, which means even when power is interrupted, the device remembers its state.
Additionally, the new transistor is inherently energy efficient. The nickelate belongs to an unusual class of materials, called correlated electron systems, that can undergo an insulator-metal transition. At a certain temperature—or, in this case, when exposed to an external field—the conductance of the material suddenly changes.
“We exploit the extreme sensitivity of this material,” says Ramanathan. “A very small excitation allows you to get a large signal, so the input energy required to drive this switching is potentially very small. That could translate into a large boost for energy efficiency.”
The nickelate system is also well positioned for seamless integration into existing silicon-based systems.
“In this paper, we demonstrate high-temperature operation, but the beauty of this type of a device is that the ‘learning’ behavior is more or less temperature insensitive, and that’s a big advantage,” says Ramanathan. “We can operate this anywhere from about room temperature up to at least 160 degrees Celsius.”
For now, the limitations relate to the challenges of synthesizing a relatively unexplored material system, and to the size of the device, which affects its speed.
“In our proof-of-concept device, the time constant is really set by our experimental geometry,” says Ramanathan. “In other words, to really make a super-fast device, all you’d have to do is confine the liquid and position the gate electrode closer to it.”
In fact, Ramanathan and his research team are already planning, with microfluidics experts at SEAS, to investigate the possibilities and limits for this “ultimate fluidic transistor.”
He also has a seed grant from the National Academy of Sciences to explore the integration of synaptic transistors into bioinspired circuits, with L. Mahadevan, Lola England de Valpine Professor of Applied Mathematics, professor of organismic and evolutionary biology, and professor of physics.
“In the SEAS setting it’s very exciting; we’re able to collaborate easily with people from very diverse interests,” Ramanathan says.
For the materials scientist, as much curiosity derives from exploring the capabilities of correlated oxides (like the nickelate used in this study) as from the possible applications.
“You have to build new instrumentation to be able to synthesize these new materials, but once you’re able to do that, you really have a completely new material system whose properties are virtually unexplored,” Ramanathan says. “It’s very exciting to have such materials to work with, where very little is known about them and you have an opportunity to build knowledge from scratch.”
“This kind of proof-of-concept demonstration carries that work into the ‘applied’ world,” he adds, “where you can really translate these exotic electronic properties into compelling, state-of-the-art devices.”
(Source: seas.harvard.edu)
Researchers identify molecule that orients neurons for high definition sensing
Many animals have highly developed senses, such as vision in carnivores, touch in mice, and hearing in bats. New research from the RIKEN Brain Science Institute has uncovered a brain molecule that can explain the existence of such finely-tuned sensory capabilities, revealing how brain cells responsible for specific senses are positioned to receive incoming sensory information.
The study, led by Dr. Tomomi Shimogori and published in the journal Science, sought to uncover the molecule that enables high acuity sensing by examining brain regions that receive information from the senses. They found that areas responsible for touch in mice and vision in ferrets contain a protein called BTBD3 that optimizes neuronal shape to receive sensory input more efficiently.
Neurons have a highly specialized shape, sending signals through one long projection called an axon, while receiving signals from many branch-like projections called dendrites. The final shape and connections to other neurons are typically completed after birth. Some neurons have dendrites distributed equally all around the cell body, like a starfish, while in others they extend only from one side, like a squid, steering towards axons that are actively bringing in information from the peripheral nerves. It was previously unknown what enables neurons to have highly oriented dendrites.
“We were fascinated by the dendrite patterning changes that occurred during the early postnatal stage that is controlled by neuronal input,” says Dr. Shimogori. “We found a fundamental process that is important to remove unnecessary dendrites to prevent mis-wiring and to make efficient neuronal circuits.”
The researchers searched for genes that are active exclusively in the mouse somatosensory cortex, the brain region responsible for their sense of touch, and found that the gene coding for the protein BTBD3 was active in the neurons of the barrel cortex, which receives input from their whiskers, the highly sensitive tactile sensors in mice, and that these neurons had unidirectional dendrites.
Using gene manipulations in embryonic mouse brain the authors found that eliminating BTBD3 made dendrites uniformly distribute around neurons in the mouse barrel cortex. In contrast, artificially introducing BTBD3 in the visual cortex of mice where BTBD3 is not normally found, reoriented the normally symmetrically positioned dendrites to one side. The same mechanism shaped neurons in the visual cortex of ferrets, which unlike the mouse contains BTBD3.
“High acuity sensory function may have been enabled by the evolution of BTBD3 and related proteins in brain development,” adds Dr. Shimogori. “Finding BTBD3 selectively in the visual and auditory cortex of the common marmoset, a species that relies heavily on high acuity vocal and visual communication for survival, and in mouse, where it is expressed in high-acuity tactile and olfactory areas, but not in low acuity visual cortex, supports this idea.” The authors plan to examine their theory by testing sensory function in mice without BTBD3 gene expression.
(Source: riken.jp)
Scientists shed light on brain computations
University of Queensland (UQ) scientists have made a fundamental breakthrough into how the brain decodes the visual world.
Using advanced electrical recording techniques, researchers at UQ’s Queensland Brain Institute (QBI) have discovered how output cells of the eye’ balls retina compute the direction of a moving object.
QBI’s Dr Ben Sivyer and Associate Professor Stephen Williams have found that dendrites – the branching process of a neuron that conducts impulses toward the cell – play a critical role in decoding images.
“In the past decade our research shows that dendrites provide neurons with powerful processing capabilities,” Associate Professor Williams said.
“However the function of dendritic processing in the real-time operation of neuronal networks has remained elusive.”
To gain further insight, the group measured electrical activity from multiple sites in retinal ganglion cells when visual stimuli moved through space.
“The retina, a thin neuronal network at the posterior part of the eyeball, is ideal for investigating the role of active dendritic integration in neuronal circuit function,” he said.
“This is because this network can be maintained intact in a dish and retains its responsiveness to natural stimuli.”
He said while it had long been known that the retinal network extracted and signalled specific aspects of visual stimuli, the new work has discovered how such responses are computed.
“We found that retinal ganglion cells compute the direction of light stimuli through exquisitely controlled local integration compartments in the dendritic tree, a finding which highlights the key function that dendrites play in brain computations,” said Associate Professor Williams.
QBI Director Professor Perry Bartlett said this new insight was vital to brain research.
“Discovering how nerve cells process information is fundamental to understanding how we learn, and to developing new strategies to enhance learning in education and in disease processes in the brain,” he said.
Queensland Minister for Science and Innovation Ian Walker congratulated Dr Sivyer and Associate Professor Williams on their internationally significant findings.
“This is another example of Queensland leading the world in health and medical research,” he said.
“Dendrite research also has flow-on implications for brain-function studies in a range of areas.
“While all of these areas are important, I will be particularly interested to see its application to dementia research, which has been a major focus for recent Queensland Government support.”
The paper, Direction selectivity is computed by active dendritic integration in retinal ganglion cells, is published in the prestigious journal Nature Neuroscience.
How problems with an Alzheimer’s protein can jam up traffic in the brain
Scientists have known for some time that a protein called presenilin plays a role in Alzheimer’s disease, and a new study reveals one intriguing way this happens.
It has to do with how materials travel up and down brain cells, which are also called neurons.
In an Oct. 8 paper in Human Molecular Genetics, University at Buffalo researchers report that presenilin works with an enzyme called GSK-3ß to control how fast materials — like proteins needed for cell survival — move through the cells.
“If you have too much presenilin or too little, it disrupts the activity of GSK-3ß, and the transport of cargo along neurons becomes uncoordinated,” says lead researcher Shermali Gunawardena, PhD, an assistant professor of biological sciences at UB. “This can lead to dangerous blockages.”
More than 150 mutations of presenilin have been found in Alzheimer’s patients, and scientists have previously shown that the protein, when defective, can cause neuronal blockages by snipping another protein into pieces that accumulate in brain cells.
But this well-known mechanism isn’t the only way presenilin fuels disease, as Gunawardena’s new study shows.
“Our work elucidates how problems with presenilin could contribute to early problems observed in Alzheimer’s disease,” she says. “It highlights a potential pathway for early intervention through drugs — prior to neuronal loss and clinical manifestations of disease.”
The study suggests that presenilin activates GSK-3ß. This is an important finding because the enzyme helps control the speed at which tiny, organic bubbles called vesicles ferry cargo along neuronal highways. (You can think of vesicles as trucks, each powered by little molecular motors called dyneins and kinesins.)
When researchers lowered the amount of presenilin in the neurons of fruit fly larvae, less GSK-3ß became activated and vesicles began speeding along cells in an uncontrolled manner.
Decreasing levels of both presenilin and GSK-3ß at once made things worse, resulting in “traffic jams” as the bubbles got stuck in neurons.
“Both GSK-3ß and presenilin have been shown to be involved in Alzheimer’s disease, but how they are involved has not always been clear,” Gunawardena says. “Our research provides new insight into this question.”
Gunawardena proposes that GSK-3ß — short for glycogen synthase kinase-3beta — acts as an “on switch” for dynein and kynesin motors, telling them when to latch onto vesicles.
Dyneins carry vesicles toward the cell nucleus, while kinesins move in the other direction, toward the periphery of the cell. When all is well and GSK-3ß levels are normal, both types of motors bind to vesicles in carefully calibrated numbers, resulting in smooth traffic flow along neurons.
That’s why it’s so dangerous when GSK-3ß levels are off-kilter, she says.
When GSK-3ß levels are high, too many motors attach to the vesicles, leading to slow movement as motor activity loses coordination. Low GSK-3ß levels appear to have the opposite effect, causing fast, uncontrolled movement as too few motors latch onto vesicles.
Both scenarios — too much GSK-3ß or too little — can result in neuronal blockages.
A brain chemical that desynchronizes the cells in the biological clock helps the clock adjust more quickly to abrupt shifts in daily light/dark schedules such as those that plague modern life.
A small molecule called VIP, known to synchronize time-keeping neurons in the brain’s biological clock, has the startling effect of desynchronizing them at higher dosages, said a research team at Washington University in St. Louis.
Far from being catastrophic, the temporary loss of synchronization actually might be useful.
Neurons knocked for a loop by a burst of VIP are better able to re-synchronize to abrupt shifts in the light-dark cycle such as those that make jet lag or shift work so miserable. It takes tumbling cells only half as long as undisturbed cells to entrain to the new schedule, the scientists say in the Oct. 28 online early edition of the Proceedings of the National Academy of Sciences.
Resynching by jarring is familiar to everyone who has whacked a flickering analog TV to get it to sync or hit the ceiling near a fluorescent light in the hope that its ballast starts buzzing.
The scientists hope to find a way to coax the brain into releasing its own stores of VIP or to find other ways to deliberately cause tumbling so the body’s clock will reset to a new time. Such a treatment might help travelers, shift works and others who overtax the biological clock’s ability to entrain to environmental cues.
The finding is the latest to emerge from the lab of Erik Herzog, PhD, who has studied the body’s time-keeping mechanisms for 13 years at Washington University in St. Louis. His focus is on understanding the clock, but because most of us live against our biological clocks and research shows this leads to health problems ranging from obesity to depression, his work is likely to have practical payoffs.
Timing is everything
The master circadian clock in mammals is a knot of 20,000 nerve cells roughly the size of a quarter of a grain of rice called the suprachiasmatic nucleus (SCN). Each neuron in the SCN keeps time, but because they’re different cells, they have slightly different rhythms. Some run a bit fast and others a bit slow.
“They’re like a society where each cell has its own opinion on what time of day it is,” said Herzog, a profesor of biology in Arts & Sciences. “They need to agree on the time of day in order to coordinate daily rhythms in alertness and metabolism.”
The cells talk to one another through a molecule called VIP (vasoactive intestinal polypeptide), a small string of amino acids that they release and receive. It’s through VIP that cells tell one another what time they think it is, Herzog said. If you get rid of VIP or the receptor for VIP, the cells lose synchrony.
“We were trying to understand exactly when VIP is released and how it synchronized the cells,” Herzog said, “and Sungwon An, then a graduate student in my lab, discovered that when there was extra VIP around, the cells lost synchrony.
“That was really surprising for us,” he said. “We did a lot of experiments just to make sure the VIP we had bought wasn’t contaminated in some way.”
It turned out the effect was real. Above a critical level, the more VIP was released, the more desynchronized the cells became. “It’s almost as if at higher doses the cells become blind to the information from their neighbors,” Herzog said.
“Then we thought: ‘Well, if the cell rhythms are messed up and out of phase, the system may be more sensitive to environmental cues than it would be if all the cells were in sync.’” If it was more sensitive, it might be better able to adjust to the abrupt schedule shifts that characterize modern life.
They were encouraged in this line of thinking by a simulation of the SCN created by Linda Petzold, Kirsten Meeker, Rich Harang and Frank Doyle, all chemical engineers at the University of California, Santa Barbara. The numerical model predicted that increasing VIP would lead to phase tumbling (less synchrony) and accelerated entrainment.
Rapid entrainment to environmental cues is important, Herzog explained. The master clock has evolved to adjust to slow seasonal changes in light/dark schedules, but not to abrupt ones that are built into the fabric of modern life. Even the seemingly benign one-hour shift for daylight savings time increases the risk of fatal car crashes and of heart attacks.
“We were curious to see whether adding extra VIP would improve the ability of biological clocks to make big adjustments,” Herzog said. An, together with graduate student Cristina Mazuski and research scientist Daniel Granados-Fuentes, showed that a shot of VIP did in fact accelerate entrainment to a new light schedule.
“We found that in mice we could cut ‘jet lag’ in half by giving them a shot of VIP the day before we ‘flew them to a new time zone,’ by shifting their light schedule,” Herzog said.
“That’s really exciting, “ Herzog said. “This is the first demonstration that giving a bit more of a substance the brain already makes actually improves the way the circadian system functions. “
“We’re taking the system the brain uses to entrain to changes in the seasons and goosing it a bit so that it can adjust to bigger shifts in the light schedule,” he said.
“We’re hoping we’ll be able to find a way to coax the brain into releasing its own stores of VIP or a light trigger or other signal that mimics the effects of VIP,” Herzog said.
Neuroscientists discover new ‘mini-neural computer’ in the brain
Dendrites, the branch-like projections of neurons, were once thought to be passive wiring in the brain. But now researchers at the University of North Carolina at Chapel Hill have shown that these dendrites do more than relay information from one neuron to the next. They actively process information, multiplying the brain’s computing power.
“Suddenly, it’s as if the processing power of the brain is much greater than we had originally thought,” said Spencer Smith, PhD, an assistant professor in the UNC School of Medicine.
His team’s findings, published October 27 in the journal Nature, could change the way scientists think about long-standing scientific models of how neural circuitry functions in the brain, while also helping researchers better understand neurological disorders.
Axons are where neurons conventionally generate electrical spikes, but many of the same molecules that support axonal spikes are also present in the dendrites. Previous research using dissected brain tissue had demonstrated that dendrites can use those molecules to generate electrical spikes themselves, but it was unclear whether normal brain activity uses those dendritic spikes. For example, could dendritic spikes be involved in how we see?
The answer, Smith’s team found, is yes. Dendrites effectively act as mini-neural computers, actively processing neuronal input signals themselves.
Directly demonstrating this required a series of intricate experiments that took years and spanned two continents, beginning in senior author Michael Hausser’s lab at University College London, and being completed after Smith and Ikuko Smith, PhD, DVM, set up their own lab at the University of North Carolina. They used patch-clamp electrophysiology to attach a microscopic glass pipette electrode, filled with a physiological solution, to a neuronal dendrite in the brain of a mouse. The idea was to directly “listen” in on the electrical signaling process.
“Attaching the pipette to a dendrite is tremendously technically challenging,” Smith said. “You can’t approach the dendrite from any direction. And you can’t see the dendrite. So you have to do this blind. It’s like fishing but all you can see is the electrical trace of a fish.” And you can’t use bait. “You just go for it and see if you can hit a dendrite,” he said. “Most of the time you can’t.”
But Smith built his own two-photon microscope system to make things easier.
Once the pipette was attached to a dendrite, Smith’s team took electrical recordings from individual dendrites within the brains of anesthetized and awake mice. As the mice viewed visual stimuli on a computer screen, the researchers saw an unusual pattern of electrical signals – bursts of spikes – in the dendrite.
Smith’s team then found that the dendritic spikes occurred selectively, depending on the visual stimulus, indicating that the dendrites processed information about what the animal was seeing.
To provide visual evidence of their finding, Smith’s team filled neurons with calcium dye, which provided an optical readout of spiking. This revealed that dendrites fired spikes while other parts of the neuron did not, meaning that the spikes were the result of local processing within the dendrites.
Study co-author Tiago Branco, PhD, created a biophysical, mathematical model of neurons and found that known mechanisms could support the dendritic spiking recorded electrically, further validating the interpretation of the data.
“All the data pointed to the same conclusion,” Smith said. “The dendrites are not passive integrators of sensory-driven input; they seem to be a computational unit as well.”
His team plans to explore what this newly discovered dendritic role may play in brain circuitry and particularly in conditions like Timothy syndrome, in which the integration of dendritic signals may go awry.
Grasshopper Mice Are Numb to the Pain of the Bark Scorpion Sting
The painful, potentially deadly stings of bark scorpions are nothing more than a slight nuisance to grasshopper mice, which voraciously kill and consume their prey with ease. When stung, the mice briefly lick their paws and move in again for the kill.
The grasshopper mice are essentially numb to the pain, scientists have found, because the scorpion toxin acts as an analgesic rather than a pain stimulant.
The scientists published their research this week in Science.
Ashlee Rowe, lead author of the paper, previously discovered that grasshopper mice, which are native to the southwestern United States, are generally resistant to the bark scorpion toxin, which can kill other animals.
It is still unknown why the toxin is not lethal to the mice.
“This venom kills other mammals of similar size,” said Rowe, Michigan State University assistant professor of neuroscience and zoology. “The grasshopper mouse has developed the evolutionary equivalent of martial arts to use the scorpions’ greatest strength against them.”
Rowe, who conducted the research while at The University of Texas at Austin, and her colleagues ventured into the desert and collected scorpions and mice for their experiments.
To test whether the grasshopper mice felt pain from the toxin, the scientists injected small amounts of scorpion venom or nontoxic saline solution in the mice’s paws. Surprisingly, the mice licked their paws (a typical toxin response) much less when injected with the scorpion toxin than when injected with a nontoxic saline solution.
“This seemed completely ridiculous,” said Harold Zakon, professor of neuroscience at The University of Texas at Austin. “One would think that the venom would at least cause a little more pain than the saline solution. This would mean that perhaps the toxin plays a role as an analgesic. This seemed very far out, but we wanted to test it anyway.”
Rowe and Zakon discovered that the bark scorpion toxin acts as an analgesic by binding to sodium channels in the mouse pain neurons, and this blocks the neuron from firing a pain signal to the brain.
Pain neurons have a couple of different sodium channels, called 1.7 and 1.8, and research has shown that when toxins bind to 1.7 channels, the channels open, sodium flows in and the pain neuron fires.
By sequencing the genes for both the 1.7 and 1.8 sodium channels, the scientists discovered that channel 1.8 in the grasshopper mice has amino acids different from mammals that are sensitive to bark scorpion stings, such as house mice, rats and humans. They then found that the scorpion toxin binds to one of these amino acids to block the activation of channel 1.8 and thus inhibit the pain response.
“Incredibly, there is one amino acid substitution that can totally alter the behavior of the toxin and block the channel,” said Zakon.
The riddle hasn’t been completely solved just yet, though, Rowe said.
“We know the region of the channel where this is taking place and the amino acids involved,” she said. “But there’s something else that’s playing a role, and that’s what I’m focusing on next.”
Some resistance to prey toxins in mammals has been found in other species. The mongoose, for example, is resistant to the cobra. And naked mole rats’ eyes do not burn in pain when carbon dioxide builds up in their underground tunnels.
This study, however, is the first to find that an amino acid substitution in sodium channel 1.8 can have an analgesic effect.
Rowe said studies such as this could someday help researchers target these sodium channels for the development of analgesic medications for humans.
Brainpower applied to understanding of neural stem cells
How do humans and other mammals get so brainy? USC researcher Wange Lu and his colleagues shed new light on this question in a paper published in the journal Cell Reports on Oct. 24.
The researchers donned their thinking caps to explain how neural stem and progenitor cells differentiate into neurons and related cells called glia. Neurons transmit information through electrical and chemical signals; glia surround, support and protect neurons in the brain and throughout the nervous system. Glia do everything from holding neurons in place to supplying them with nutrients and oxygen to protect them from pathogens.
By studying the embryo neural stem cells of mice in a petri dish, Lu and his colleagues discovered that a protein called SMEK1 promotes the differentiation of neural stem and progenitor cells. At the same time, SMEK1 keeps these cells in check by suppressing their uncontrolled proliferation.
The researchers also determined that SMEK1 doesn’t act alone: It works in concert with Protein Phosphatase 4 to suppress the activity of PAR3, a third protein that discourages neurogenesis — the birth of new neurons. With PAR3 out of the picture, neural stem cells and progenitors are free to differentiate into new neurons and glia.
“These studies reveal the mechanisms of how the brain keeps the balance of stem cells and neurons when the brain is formed,” said Wange Lu, associate professor of biochemistry and molecular biology at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “If this process goes wrong, it leads to cancer or mental retardation or other neurological diseases.”
Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step toward harnessing the cells’ therapeutic potential. This could offer new hope for patients with Alzheimer’s, Parkinson’s and many other currently incurable diseases.